The human immunodeficiency virus (HIV) causes persistent infection and chronic progressive disease involving multiple organ systems but the pathogenesis of the lesions is not understood. Development of lesions correlates with a high degree of virus gene expression of macrophages in pathologically affected tissues. Among non-human primates, different species of African monkeys are naturally infected with indigenous lentiviruses, but these agents are apathogenic in these animals. However, inoculation of Asian macaques with the viruses results in disease that resembles the HIV disease complex. Lesions in diseased macaque tissues are accompanied by extensive virus replication in tissue macrophages, similar to that seen in human tissues. In this application, we ask if there are cell-culture correlates that can predict pathogenicity of these viruses. Our central hypothesis is that host macrophages, in addition to T4 lymphocytes, must be susceptible to productive replication of viruses that cause disease. This predicts that host species of animals that do not develop disease will have T4 lymphocytes permissive for virus replication but macrophages will be non- permissive. On the other hand, species that do develop disease will have permissive lymphocytes and permissive macrophages. We will test the hypothesis in established model systems of apathogenic infection in African monkeys and fulminant disease in macaques. Lymphocytes and macrophages from uninfected animals will be tested for permissiveness of virus replication and similar cells from infected animals will be examined for evidence of productive virus replication. Multiple parameters of infection in the cell cultures will include tests for viral RNA, viral proteins, virions, and virus infectivity. We will then use this strategy to test permissiveness of cells of different macaque species to infection with lentiviruses of unknown pathogenicity. Fully permissive systems will be tested for confirmation of pathogenicity in limited experiments in macaques at the Yerkes Primate Center. The project will combine expertise in lentivirus-macrophage biology, ultrastructural analysis and existing expertise of lentivirus pathogenesis in macaques at the Yerkes Primate Center and access to exotic species of non-human primates. These experiments will provide a valuable, relatively inexpensive test system for identification of new models of AIDS and contribute to the further understanding of lentivirus disease.